Insulin resistance in human obesity, diabetes mellitus and a variety of other clinical situations is generally associated with hyperinsulinemia and hyperglycemia alone or in combination. The extent to which these changes n plasma insulin and plasma glucose concentrations result from and/or contribute to insulin resistance is unclear. Therefore, experiments proposed in this application will examine the influence of plasma insulin and glucose concentrations per se on insulin action and on insulin receptor and postreceptor function in normal, obese and diabetic man. Insulin action will be assessed by determining insulin dose-response curves for glucose disposal using sequential infusions of insulin in conjunction with the euglycemic clamp technique. The relationship of alterations in insulin receptor and postreceptor function to changes in insulin action will be evaluated by relating data obtained from the insulin dose-response curves to monocyte and erythrocyte insulin receptor binding. Involvement of hepatic and extrahepatic tissues will be estimated by assessing changes in glucose production and glucose utilization (measured isotopically) during the insulin dose-response studies. Using these techniques, the effects of increasing plasma insulin concentrations in nonobese man (produced by an exogenous infusion of insulin) and of decreasing plasma insulin concentrations in hyperinsulinemic obese man (produced by infusion of somatostatin, fasting or weight loss) will be evaluated. Differences in insulin action and in insulin receptor function and postreceptor function between euinsulinemic and hyperinsulinemic nonobese noninsulin dependent diabetic subjects and between obese diabetic anad nondiabetic subjects will be examined. Finally, the effects of antecedent and hyperglycemia on insulin action will be determined. These studies should provide new insight regarding the mechanisms of insulin resistance and the contribution of changes of insulin receptor and postreceptor function to alterations in insulin action.